Cardiolipin-mimic lipid nanoparticles without antibody modification delivered senolytic in vivo CAR-T therapy for inflamm-aging
mRNA-based in vivo chimeric antigen receptor (CAR)-T cell engineering offers advantages over ex vivo therapies, including streamlined manufacturing and transient expression. However, current delivery methods require antibody-modified vehicles with manufacturing challenges. In this study, inspired by cardiolipin, we identify cardiolipin-like di-phosphoramide lipids that improve T cell transfection without targeting ligands, both in vitro and in vivo. The T cell-favored tropism is likely due to the lipid's packing, shape, and rigidity. Encapsulating circular RNA further prolongs mRNA expression in the spleen and T cells. Using PL40 lipid nanoparticles, we deliver mRNA encoding a CAR targeting the senolytic and inflammatory antigen urokinase-type plasminogen activator receptor (uPAR), alleviating uPAR-related liver fibrosis and rheumatoid arthritis (RA). Single-cell sequencing in humans confirms uPAR's relevance to senescence and inflammation in RA. To facilitate clinical translation, we screen and humanize single-chain variable fragments (scFvs) against uPAR, establishing a PL40 mRNA-encoded humanized uPAR CAR with potential for treating aging-inflamed disorders.
Authors
- Xun Gui (ORCID: https://orcid.org/0000-0002-5070-3527)
- Wei You (ORCID: https://orcid.org/0000-0003-0071-6730)
- Min Gao (ORCID: https://orcid.org/0000-0002-4952-5399)
- Zhiwei Li (ORCID: https://orcid.org/0000-0003-2239-2802)
- Beidi Chen (ORCID: https://orcid.org/0000-0002-7586-1855)
- Hailong Zhao (ORCID: https://orcid.org/0000-0002-3431-6228)
- Yanyun Hao (ORCID: https://orcid.org/0009-0001-9186-5784)
- Jiang‐Miao Hu (ORCID: https://orcid.org/0000-0002-9013-8489)
- Xiaoqing Hu (ORCID: https://orcid.org/0000-0001-9824-1109)
- Peishi Rao
- Yuanjie Zhang (ORCID: https://orcid.org/0000-0002-3661-3170)
- Xiaolin Sun (ORCID: https://orcid.org/0000-0001-9709-1532)
- Lei Miao (ORCID: https://orcid.org/0000-0001-6414-4773)
- Zihan Zhang (ORCID: https://orcid.org/0000-0001-6667-1200)
- Liang Zhang (ORCID: https://orcid.org/0000-0002-2279-2657)
- Rui Wang
- Yu Wang (ORCID: https://orcid.org/0000-0003-3151-0778)
- Yun Yang (ORCID: https://orcid.org/0000-0002-9986-5930)
- Rui Peng (ORCID: https://orcid.org/0000-0002-1654-0402)
- Demin Zhou (ORCID: https://orcid.org/0000-0003-0339-0959)
- Ming Lu (ORCID: https://orcid.org/0000-0003-4639-7851)
- Mi Deng
- Buyao Li
- Bin Ma (ORCID: https://orcid.org/0009-0001-9423-4734)
Institutions
- Chinese Academy of Sciences (CN)
- Peking University (CN)
- Beijing Jishuitan Hospital (CN)
- Bioscience (China) (CN)
- Peking University Cancer Hospital (CN)
- Beijing National Laboratory for Molecular Sciences (CN)
- Health Biomed (China) (CN)
- Peking University People's Hospital (CN)
- Suzhou Research Institute (CN)
- Peking University International Hospital (CN)
- Peking University Third Hospital (CN)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2025-07-01
- DOI
- https://doi.org/10.1016/j.xcrm.2025.102209
- Citations
- 23
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 24.04
Funders
- National Natural Science Foundation of China
- Natural Science Foundation of Beijing Municipality
- Beijing Municipal Science and Technology Commission
- Peking University Health Science Center